This renewal proposal outlines four specific objectives for research on several areas of carbohydrate biosynthesis and metabolism. Its broad, long-term objectives are to advance the fundamental chemical and biochemical understanding of carbohydrate metabolism and the role of carbohydrates in a variety of disease states. Specific aims include the following: (1)The synthesis of amidrazone sugar analogs should lead to potent transition-state structural mimics which inhibit carbohydrate-processing enzymes known as glycosidases. Several new monosaccharide amidrazones will also be prepared for use as ligands for genetic engineering of catalytically active artificial exoglycosidases and synthetic lectins which bind monosaccharides. (2)Several novel glycosphingolipid (GSL) analogs will be synthesized and tested as inhibitors of GSL biosynthesis. Such inhibitors should prove useful in elucidating the role of GSLs in cancer cell metabolism. (3)Enantioselective total syntheses are proposed for several unusual polyhydroxycyclopentanes and cyclohexanes which are potent glycosidase inhibitors. Targets include mannostatins A & B, allosamidin, valienamine and pseudo-alpha-galactopyranose. (4)Rational chiral syntheses of several novel heteroglycosides are proposed. These unnatural structures are expected to inhibit or inactivate specific glycosidases according to sound biological rationales, but in unusual new ways.